1. Field of the Invention
This invention relates to a process for the preparation of 1,4-dioxane-2,5-diones which are useful for the preparation of degradable polymers.
2. Technical Background
The present invention provides a process for the preparation of 1,4-dioxane-2,5-diones, represented by Formula I, wherein each R is independently H or hydrocarbyl. These compounds are useful as precursors in the preparation of degradable polymers. ##STR1##
Compounds of Formula I are cyclic dimers of .alpha.-hydroxycarboxylic acids. In principle, two molecules of .alpha.-hydroxycarboxylic acids can condense to produce a compound of Formula I and two molecules of water. However, the direct formation of compounds of Formula I from .alpha.-hydroxycarboxylic acids is generally of limited preparative value, since it is most often the case that self-condensation of the .alpha.-hydroxycarboxylic acids forms a complex mixture of linear and cyclic oligomers resulting in poor yields. Acta Chem. Scand., Ser. B, 34, 633-6, 1980. This direct method affords poor yields of desired product even under dilute conditions where cyclization of a linear intermediate might be favored: 3,6-diphenyl-1,4-dioxane-2,5-dione was prepared from mandelic acid and a catalytic amount of p-toluene-sulphonic acid in refluxing benzene with water removal in only 11% yield with much oligomer formation. Chem. Mater., 2, 248-54, 1990. In what must be considered an exception to the rule, 3,3,6,6-tetraphenyl-1,4-dioxane-2,5-dione was similarly prepared from diphenylacetic acid in 93% yield. Synth. Commun., 17, 1919-28, 1987.
Compounds of Formula I have been more commonly prepared in a two-step reaction. In the first step, .alpha.-hydroxyacids are heated with the removal of water to form oligomers. In the second step, thermolysis of the oligomer is performed in the liquid phase in the presence of various catalysts at temperatures near 250.degree. C. The compound of Formula I formed by this process is generally distilled from the reaction mixture as it is formed and is then crystallized from an appropriate solvent. Prior to crystallization, the crude product typically contains a significant amount of acidic impurities. This process suffers from excessive tar formation, low yields, and slow production rates. U.S. Pat. No. 4,835,293 discloses an improvement on this method whereby an inert gas is used to carry the product from the reaction mixture to a solvent system. U.S. Pat. No. 4,727,163 discloses an improvement whereby the thermolysis is performed on a block polymer comprising a thermally-stable polyether core with an .alpha.-hydroxyacid polymerized onto the core.
An alternative method for the production of compounds of Formula I involves the reaction of a carboxylic acid salt with a halide. EP 339,882 discloses that salts of 2-halopropionic acids, when heated at ca. 200.degree. C. in organic solvents, form crude lactide from which lactide of high purity is obtained, after crystallization, in yields of approximately 15%. U.S. Pat. No. 3,763,190 discloses the preparation of 1,4-dioxane- 2,5-dione by heating sodium O-(chloroacetyl)glycolate at 125.degree.-240.degree. C. with sublimation of the products and purification by fractional vacuum sublimation at 0.03 torr and 25.degree. C. Compounds of Formula I are also prepared by distillation of the sodium salts of the appropriate 2-bromocarboxylic acids. Org. Mass Spectrom., 2, 893-900, 1969.
Compounds of Formula I have also been obtained from methylarsino-subsituted .alpha.-hydroxy carboxylate esters. Chem.-Ztg., 112, 125-7, 1988. Reaction of diphenylacetic acid in concentrated H2SO4 yields compounds of Formula I. J. Am. Chem. Soc., 108, 5237-42, 1986. Thermal or photochemical reaction of .alpha.-diazo ketones with molecular oxygen yields compounds of Formula I. J. Org. Chem., 38, 1602-5, 1973. Compounds of Formula I are obtained as a by-product in the manufacture of methacrylic acid via H.sub.2 SO.sub.4 hydrolysis of methacrylamide. Zh. Prikl. Khim. (Leningrad), 53, 423-7, 1980.
The above methods have been used for the preparation of symmetrically 3,6-substituted 1,4-dioxane-2,5-diones (compounds of Formula I in which the substituents of carbon 3 are equivalent to the substituents at carbon 6). While unsymmetrically 3,6-substituted 1,4-dioxane-2,5-diones (compounds of Formula I in which at least one R group on the 3-carbon is different from at least one R group on the 6-carbon) can be obtained by the processes outlined above, the reactions would be expected to lead to a mixture of different 1,4-dioxane-2,5-diones. The separation of such a mixture would be difficult and would require extensive and costly purification procedures. For example, U.S. Pat. No. 4,033,938 discloses that thermolytic cracking of an oligomer prepared from glycolic acid and lactic acid provided a mixture of 1,4-dioxane-2,5-dione, 3-methyl-1,4-dioxane-2,5-dione and 3,6-dimethyl-1,4-dioxane-2,5-dione from which pure (&gt;99%) 3-methyl-1,4-dioxane-2,5-dione was obtained only after repeated distillation. ##STR2##
Unsymmetrically 3,6-substituted 1,4-dioxane-2,5-diones have been prepared from compounds of Formula II (X=Cl or Br; R.sup.2, R.sup.3, R.sup.4, and R.sup.5 =H, alkyl or aralkyl). U.S. Pat. No. 4,033,938 discloses the production of 3-methyl-1,4-dioxane-2,5-dione and 3,3-dimethyl-1,4-dioxane-2,5-dione from O-(chloroacetyl) lactic acid and O-(chloroacetyl)-2-hydroxyisobutyric acid, respectively, in yields of approximately 25%. In each case, an arduous purification procedure was employed. The preparation of 3-methyl-1,4-dioxane-2,5-dione from O-(2-bromopropionyl)glycolic acid has been reported. A. C. Ibay (Army Inst. Dent. Res., Washington, DC); Report, Order No. AD-A199413; Gov. Rep. Announce. Index (U.S.) 1989, 89 (3). More recently, a reaction of dilute O-(chloroacetyl)lactic acid in dimethylformamide (2%, w/v) and a weak base was reported to give 3-methyl-1,4-dioxane-2,5-dione in yields as high as 87%. Chem. Express, 5, 149-52, 1990. A number of compounds of Formula II were prepared from .alpha.-bromocarboxylic acid chlorides and .alpha.-hydroxycarboxylic acids to give unsymmetrically 3,6-substituted 1,4-dioxane-2,5-diones in yields of 60-85% (Angew. Chem., 91, 329-30, 1979).
There exists a need for a process capable of producing 1,4-dioxane-2,5-diones cleanly, in high yield and without the necessity of extensive and costly purification procedures. In addition the process should provide unsymmetrically 3,6-substituted 1,4-dioxane-2,5-diones as well as symmetrically 3,6-substituted 1,4-dioxane-2,5-diones. It is the object of the present invention to provide such a process.